The broad objective of this research proposal is to seek a better understanding, at the molecular level, of the biochemical events which may be associated with the pathogenesis of emphysema, and thus provide a rational basis for the design of drugs that can be used for the effective treatment of this disease. Particular emphasis will be placed on (1) the interaction of the alpha 1-trypsin inhibitor with proteinases which may be responsible for the destruction of lung tissue, and (2) structural differences between normal variants of the alpha 1-trypsin inhibitor and the genetic variants associated with emphysema. This problem will be approached along the following lines: 1) The purification and detailed physicochemical characterization of the alpha 1-trypsin inhibitor of human blood serum; 2) The purification and detailed characterization of leucocyte proteinases capable of digesting lung tissue. Special effort will be devoted to the design of synthetic inhibitors of these enzymes; 3) A study of the mechanism of interaction of alpha 1-trypsin inhibitor with leucocyte proteinases with special emphasis on the chemical nature of the proteinase binding site of the inhibitor. 4) Amino acid sequence and carbohydrate composition of normal and abnormal variants of the alpha 1-trypsin inhibitor.